Category: Preclinical Development
Purpose: Irbesartan is an angiotensin II receptor antagonist used to treat hypertension. The primary objective of the following work was to develop a PBPK dog model for orally administered (immediate release) Irbesartan (IRBS) and link the predicted unbound IRBS plasma concentration – time (Cp-t) profiles to the reduction in systolic blood pressure (SBP) of healthy dogs.
Methods: Simcyp Dog (Version 18) is a virtual PBPK dog model with default anatomy and physiology values based on a 10 kg healthy beagle dog. The PBPK model for IRBS was parameterised as follows; absorption was predicted by the MechPeff model1 based on intestinal passive regional permeability, volume of distribution at steady state was predicted using the Rodgers & Rowland full PBPK method and clearance was calculated from in vivo studies2,3 using the retrograde approach. A formulation gastric emptying lag time of 1.5 hours was included in the model to recover the delayed time to maximum drug plasma concentration (tmax). Due to lack of information, the particle size radius of the IRBS was set at 100 µm based on sensitivity analysis to recover the Cmax and tmax of the 2 mg/kg dose. IRBS Cp-t profiles were predicted after single oral dose administration of immediate release (2 mg/kg, 5 mg/kg) and suspension (30 mg/kg) dosage forms. Predicted simulations were compared with observed data2,3. The immediate release dose was in the form of capsules administered orally by mouth and the suspension formulation was administered intra-gastrically. Predicted unbound IRBS Cp-t profiles were linked to reduction in SBP (mm Hg) for the 5 mg/kg dosage regimen using a simple Emax model. Emax model parameters (Emax and EC50) were optimized for 5 mg/kg dose. The model can then be used to predict the reduction in SBP for 2 and 30 mg/kg doses and compare to observed SBP response curves. (E0: 128 mmHg; EC50: 0.0123 µM; Emax: -21.2 mmHg).
Results: Simulated IRBS Cp-t profiles were in good agreement with published literature. Table 1 shows the predicted and observed PK/PD parameters for IRBS after administration of 2, 5 and 30 mg/kg doses. The Cmax and tmax for all the three dose levels was within 1.3-fold of the observed values. The AUCinf values for the 2 and 5 mg/kg doses were reasonably well predicted whereas the AUCinf value for the 30 mg/kg dose was slightly under predicted compared to the observed value, albeit still below 1.5 – fold. The predicted AUCR for the SBP response was 2888 mmHg.hr compared to the observed value of 2894 mmHg.hr.
Conclusion: The Simcyp virtual dog model is reasonably successful in predicting IRBS Cp-t profiles after oral administration of immediate release capsules and suspension formulation in beagles. The delayed value of tmax observed in the in vivo data, (accommodated by a delay in gastric emptying time in the simulations) is usually not characteristic of immediate release capsule or suspension formulations. The reduction in SBP was well predicted for the 5 mg/kg dose by using a simple Emax model. SBP reduction for other doses could be predicted but not verified due to variable baseline SBP.
Reference:  Pade et al. Biopharm. Drug Dispos. 38(2): 94-114 (2017);  Carlucci et al. Polish Journal of Vet. Sciences. 16 (3): 555-561 (2013);  Huang et al. Eur J Drug Metab Pharmacokinet.30 (1) 121-125 (2005).
Sibylle Neuhoff– Sheffield, England, United Kingdom
Khaled Abduljalil– Sheffield, England, United Kingdom
Masoud Jamei– Senior Vice President of R&D, Certara UK Limited, Simcyp Division, Sheffield, England, United Kingdom